1、Benefits of Tight Blood Pressure Control in Diabetic patients with Hypertension,2011, June 03, 嚴逢杰醫師,Diabetes Care, Volume 34, Supplement 2, May 2011,Diabetic patients are characterized by a significantly higher risk of CV events compared with nondiabetic individuals, with diabetes itself being cons
2、idered a CVD equivalent. (1-4) Observational data from UKPDS reported a continuous positive correlation between the level of SBP and the risk of developing macro- and microvascular complications in T2D pts, without any evidence of BP threshold level. (5) With known synergistic interaction of hyperte
3、nsion and diabetes as CV risk, optimal BP control is particularly important in hypertensive pt with DM. (7-11),The UKPDS was formally close in 2007, i.e., 30 years after its outset(開端）, thus being one of the longest trials ever made. The main aim of this study was to establish whether, in pt with T2
4、D, intensive glycemic control might reduce the risk of vascular complications, and its result have profoundly influenced the management of T2D. (12-14) The Hypertension in Diabetes Study (HDS), embedded in the UKPDS in 1987, confirmed that hypertension is a major risk factor for CVD in T2D pt (16-18
5、) and addressed the importance of a tight BP control in hypertensive pt with T2D(19).,Legacy Effect of Earlier Glucose Control,The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med 2005;353:2643-2653,Cumul
6、ative Incidence of the First of Any of the Predefined Cardiovascular Disease Outcomes (Panel A) and of the First Occurrence of Nonfatal Myocardial Infarction, Stroke, or Death from Cardiovascular Disease (Panel B),42%,57%,Legacy Effect,NEJM 2008; 359:1565-76,BMJ 1998;307: 703-13,Median duration of f
7、ollow-up was 8.4 yrs. Tight vs conventional: 143/82 vs 154/88 mmHg,DM related events 24,DM related death 32,Microvascular 37,Stroke 44%,Posttrial f/u median duration: 8 yrs,No Legacy effect,Possible role of suboptimal BP lowering,Although prospective studies have showed that small reductions in BP r
8、educe the CV events, the BP target of 150/85 mmHg considered for the tight BP control was by far above the current BP target of 130/80 in all major guideline. (29-32) Subsequent studies have assess the benefit associated with lower BP targets, however, no extended follow-up was conducted in any of t
9、hem. (34-38),Influence of previous history of diabetes and delayed start of antihypertensive treatment,The HDS started 10 years after the original study. Therefore, the pt in the HDS were not actually newly diagnosed. During these 10 yrs, additional irreversible organ damage has likely developed, le
10、ading to a higher level of CV risk. A recent systemic review comparing the reductions in CV events, including pt with different baseline of CV risk, showed that the duration of disease with regard to time treatment started may influence outcome. Once organ damage is advanced, a high incidence of CV
11、events persisted despite intensive BP lowing ( ceiling effect) (39). Finally, the importance of an early start of tx to optimize pt protection was suggested.,Factorial design of the study and impossibility to control for the effects of background interventions,When posttrial follow-up started, the m
12、edian value of HbA1C at baseline was significantly higher in the tight control group than in the less tight control group. ( 8.3% vs 7.5%). Because the data from the main study and from HDS were analyzed independently following a factorial design, it was not possible to control for the effect of pot
13、ential confounders, such as glycemic level.,Use of older less efficacious antihypertensive agents with adverse effects on glucose homeostasis,61% of pts in the tight control group were on 2 or more antihypertensive agents (compared with 36% in the less tight control group), a greater use of thiazide
14、 diuretics in tight control group could not be ruled out. Thus, its likely that the adverse metabolic effects reported for both atenolol and thiazide diuretics developed, as further suggested by the significant increases in mean glucose levels (1.0 vs 0.7 mmlo/L) and in body weight (2.3 vs 0.5kg).,R
15、ole of a shorter median time of randomized interventions in HDS,The randomized antihypertensive intervention in the HDS was only conducted during a median of 4 years. Although this was enough for benefits in CV outcomes in the short term, it was probably not long enough for tight BP control for conf
16、er a protecting legacy effect.,Small differences in BP between tight and less tight BP control,The difference between mean BP levels achieved over the 4 years of the randomized intervention for the tight and less tight BP control was relatively small ( 143/82 vs 154/88 mmHg), and this might have con
17、tributed to the lack of differences.,Absence of BP legacy or only a time-to-effect relationship between BP control and CV outcome?,BP reduction, per se, is the main determinant of the prognostic benefit of antihypertensive tx. Most trials in hypertension have shown the occurrence (發生） of a short tim
18、e-to-effect relationship between BP control and the improved in CV outcome. (table) A comprehensive review of 14 randomized trials on antihypertensive drugs concluded that the reductions in stroke and CHD appear rapidly after starting treatment. (51),In VALUE trail, reaching BP control by the 6th mo
19、nth was associated with significant benefits. It also showed that the BP response predicted events and survival already after only 1 month of active treatment. (52) Most studies have confirmed that benefits of antihypertensive tx usually appear in the short term. (33-38, 44) The effectiveness of tig
20、ht BP control was first shown by the HOT trail. After a mean of 3.8 yrs of f/u, subgroup analysis showed that T2D pt randomized to a target DBP =80 had a significant reduction of 51% when compared with the target of =90 mmHg. (20),The HOPE study embedded the MICRO-HOPE substudy, which investigated t
21、he effects of the addition of an ACEI (10mg/d Ramipril) to the current medical regimen. After a median of 4.5 yrs of f/u, a significant reduction of 25% in primary outcomes was reported, with significant reduction in the risk of MI by 22%, of stroke by 33%, and of CV death by 37%. (44) The ADVANCE s
22、tudy also assessed the effects of ACEI/diurectics. After a mean 4.3 yrs of f/u, the relative risk was significant reduced by 9% for macro and microvascular events. These modest (溫和）reductions are easily explained by the fact that the difference in BP between the two groups was small. (5.6 and 2.2 mm
23、Hg for SBP and DBP).,Thus, there are unequivocal（毫無疑問的） evidence that in both hypertensive pt with and without DM, benefits of anti-HTN tx on major CV outcomes usually appear shortly after treatment implementation. On the other hand, with regard to the long-term effects of an initial tx, the evidenc
24、e is rather limited. Strong data in favor of long-term benefits of an early start of anti-HTN tx come from the Syst-Eur study.,In Syst-Eur study, elderly pt with isolated systolic HTN after 2 yrs of randomized tx with nitrendipinde or placebo were invited. After 4 yrs of f/u ( 6yrs after randomizati
25、on), pt with early anti-HTN tx had a significantly greater reduction in the risk of stroke (28%), CV complications (15%), and total mortality (13%). In the 492 DM pt, the additional benefits were even more pronounced （表示）, with significant reductions in the risk of above mentioned by 60%, 51%, and 3
26、8%. (55) These results are in clear contrast with results of the UKPDS-HDS. Thus, it is likely that the putative(推定的） absence of a legacy effect was a result of several limitations of this study, and it dose not reflect a real lack of long-term benefit of early BP lowering in diabetes.,Conclusion,Th
27、e observations in the UKPDS-HDS might indeed seem to demonstrate the absence of a legacy effect. However, these results need to be interpreted with caution. Other factors may contribute to explain the observed loss of CV benefits, and the most important of them is likely to be a delayed start of tx,
28、 leading to an increased basal risk of CV events. Rather than focus on the possible lack of BP legacy, the interpretation should emphasize the unquestionable finding that CV protection is more likely to be effectively achieved if tight BP control is implemented early and sustained over time.,A recen
29、t critical analysis of several hypertension trials showed that the longer the disease duration before starting anti-HTN tx, the smaller the benefits in terms of CV risk reduction and the larger the residual risk remaining, even if optimal preventive measures are taken. (39) Therefore, an adequate anti-HTN tx, possibly early in the course of the disease, remains a cornerstone in the modern approach to diabetes management.,
